The overall goal of this project is to characterize the role played by MIP-1a and MIP-1b in host defense against bacterial, viral and parasite invasion. Despite medical advances, the activation of host defenses is an important determining factor in the outcome of infection. Effective antimicrobial host defense requires the generation of a vigorous inflammatory response that involves the recruitment and activation of specific leukocyte populations. These processes depend on chemotactic signals, largely supplied by a class of cytokines termed chemokines. An aim, since discovering MIP-1a and MIP-1b, two members of the chemokine family, has been to characterize the role each plays in host defense against bacterial, viral, and parasite invasion. Progress made in the prior two funding periods of this grant, in combination with the work of others in the field of chemokine biology, has revealed that b-chemokine expression is upregulated in response to many inflammatory stimuli, and that there is differential control of these molecules in several animal disease models. This control is critical because inflammatory reactions that are disproportionate to the magnitude of the immune challenge can be harmful, or even fatal, to the host. The new objective is to better define the molecular mechanisms by which the b-chemokines work together, and in opposition, to modulate the cellular and systemic responses of the host to invasion, and in particular we plan to evaluate their role, pathogenic versus protective, in three specific disease states (septic shock, HIV infection, and malaria infection) where we have shown them to be specifically upregulated. With regard to sepsis, this will be addressed by passive immunization of mice with MIP-1a versus MIP-1b specific antibodies, and by direct administration of recombinant chemokines in experimental endotoxemia. It will also be determined whether the protective effects of MIP-1b in sepsis are related to its antagonism of MIP-1a through either competition for, or downregulation of, specific chemokine receptors, or whether other mechanisms are at work. With regard to HIV infection, it will be established which molecular mechanisms lead from HIV infection to chemokine production in macrophages, and addressed why b-chemokines are not protective in macrophages, as they have been recently shown to be in T cells. With regard to malaria, where MIP-1a exerts a beneficial effect, the course of infection in MIP-1a knockout mice and wild-type mice is to be compared, as well as in mice passively administered b-chemokine-specific antibodies, in order to determine whether MIP-1b positively or negatively impacts the course of infection. Hopefully, these studies will eventually lead to the development of intervention strategies to benefit the host in times of invasion.